RNA-seq on in vitro 3D structure of Klf5-KO biliary epithelial cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE145420 | GEO | 2026/07/31
REPOSITORIES: GEO
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Project description:In other to assess functional involvement of Klf5 in DR regulation, we made liver-specific Klf5 knockout mice. Ductular reaction upon cholestatic liver injury is severely suppressed in these mice. We conducted RNA-seq analysis on the BECs from control mice and Klf5 LKO mice upon DDC injury to further elucidate the Klf5 functions.
2018-03-16 | GSE97167 | GEO
Project description:Purpose: Cholestatic liver injury is associated with intrahepatic biliary fibrosis, which can progress to cirrhosis. Resident hepatic progenitor cells (HPCs) expressing Prominin-1 (Prom1/CD133) become activated and participate in the expansion of cholangiocytes known as the ductular reaction. Previously, we demonstrated that in biliary atresia, Prom1(+) HPCs are present within developing fibrosis and that null mutation of Prom1 significantly abrogates fibrogenesis. Here, we hypothesized that these activated Prom1-expressing HPCs promote fibrogenesis in cholestatic liver injury. Methods: Using Prom1CreERT2-nLacZ/+;Rosa26Lsl-GFP/+ mice, we traced the fate of Prom1-expressing HPCs in the growth of the neonatal and adult livers and in biliary fibrosis induced by bile duct ligation (BDL). Results: Prom1-expressing cell lineage labeling with Green Fluorescent Protein (GFP) on postnatal day 1 exhibited an expanded population as well as bipotent differentiation potential towards both hepatocytes and cholangiocytes at postnatal day 35. However, in the adult liver, they lost hepatocyte differentiation potential. Upon cholestatic liver injury, adult Prom1-expressing HPCs gave rise to both PROM1(+) and PROM1(-) cholangiocytes contributing to ductular reaction without hepatocyte or myofibroblast differentiation. RNA-sequencing analysis of GFP(+) Prom1-expressing HPC lineage revealed a persistent cholangiocyte phenotype and evidence of Transforming Growth Factor-b pathway activation. Conclusion: Our data indicate that Prom1-expressing HPCs promote biliary fibrosis by activation of myofibroblasts in cholestatic liver injury.
2020-06-30 | GSE144726 | GEO
Project description:A unique pathological hallmark of chronic liver disease (CLD) is the ductular reaction, characterised by the proliferation of reactive bile ducts associated with an inflammatory infiltrate. In this study we identify the Tetraspanin family member, TSPAN6, as a novel regulator of biliary-immune cell cross talk. We initially demonstrate that TSPAN6 is expressed by biliary ductules within the ductular reaction from samples of cirrhotic human liver tissue across multiple aetiologies and significantly elevated in cholestatic liver diseases. We also confirm that it is upregulated in in vivo models of ductular reaction. Additionally, TSPAN6 protein expression demonstrated a positive correlation with the presence of infiltrating (MAC387+) macrophages. Using a human in vitro model of primary biliary epithelial cell (BEC)-monocyte cross talk, we demonstrate that TSPAN6 regulates BEC-driven monocyte activation and chemokine production. Specifically, LPS stimulation of BEC led to downstream inflammatory activation of human monocytes, with upregulation of pro-inflammatory chemokines. TSPAN6 knockdown in BEC partially reversed this in monocyte activation, with specific reduction in the chemokines CXCL1,2 and 5. Transcriptomic profiling, following TSPAN6 depletion, confirmed its involvement in membrane-associated trafficking and lipid modification pathways in biliary epithelial cells. We propose TSPAN6 as a potential organiser of epithelial signalling platforms, contributing to inflammation and regeneration, during liver injury and could therefore be a novel therapeutic target in CLD.
2026-01-31 | GSE317449 | GEO
Project description:Ductular reaction (DR) is the hallmark of cholestatic diseases manifested in the proliferation of bile ductules lined by biliary epithelial cells (BECs). It is commonly associated with increased risk of fibrosis and liver failure. The Receptor for Advanced Glycation End Products (RAGE) was identified as a critical mediator of DR during chronic injury. Yet, the direct link between RAGE-mediated DR and fibrosis as well as the mode of interaction between BECs and hepatic stellate cells (HSCs) to drive fibrosis remain elusive. Here, we delineate the specific function of RAGE on BECs during DR and its potential association with fibrosis in the context of cholestasis. Employing a biliary lineage tracing cholestatic liver injury mouse model, combined with whole transcriptome sequencing, mass spectrometry and in vitro analyses, we investigated the role for BEC-specific Rage activity in fostering a pro-fibrotic milieu. RAGE is predominantly expressed in BECs and contributes to DR. Employing mass spectrometry analyses of soluble factors of in vitro cultured wildtype and RAGE deficient BECs Notch ligand Jagged1 was found to be secreted from activated BECs in a Rage-dependent manner and signals HSCs in trans, eventually enhancing fibrosis during cholestasis.
2025-07-16 | PXD065854 | Pride
Project description:RNA-seq on in vitro 3D structure of Klf5-KO biliary epithelial cells
| PRJNA607198 | ENA
Project description:Lineage plasticity is a hallmark of pancreatic ductal adenocarcinoma (PDAC) and contributes to tumor heterogeneity and therapeutic resistance. Here, we identify KLF5 as a dynamic master regulator of epithelial lineage identity in PDAC, with dichotomous roles in promoting either classical or basal-like transcriptional programs. Through unbiased proteomic and genetic screens, we uncover the AAA+ ATPases RUVBL1 and RUVBL2 as essential coactivators of KLF5 across both lineage states. We demonstrate that ATP hydrolysis by RUVBL1/2 is required for the stable interaction with an intrinsically disordered region of KLF5, enabling its recruitment to lineage-specific enhancers and driving transcriptional regulation of identity-defining genes. Notably, small-molecule inhibitors of RUVBL1/2 ATPase activity, which have anti-PDAC activity in vivo, suppress KLF5-dependent transcription. These findings define a previously unrecognized mechanism of ATP hydrolysis-dependent transcriptional coactivation by AAA+ ATPases and highlight a potential therapeutic strategy for modulating aberrant lineage programs in cancer. This project contains files relative to a Co-IP MS with KLF5-MBP as bait.
2025-08-21 | PXD066112 | Pride
Project description:Ductular reaction (DR) is the hallmark of cholestatic diseases manifested in the proliferation of bile ductules lined by biliary epithelial cells (BECs). It is commonly associated with increased risk of fibrosis and liver failure. The Receptor for Advanced Glycation End Products (RAGE) was identified as a critical mediator of DR during chronic injury. Yet, the direct link between RAGE-mediated DR and fibrosis as well as the mode of interaction between BECs and hepatic stellate cells (HSCs) to drive fibrosis remains elusive. In this study, we aimed to delineate the specific function of RAGE on BECs during DR and its potential association with fibrosis in the context of cholestasis. Employing a biliary lineage tracing cholestatic liver injury mouse model, combined with whole transcriptome sequencing and in vitro analyses, we revealed the central role of BEC-specific Rage activity in fostering a pro-fibrotic milieu. RAGE is predominantly expressed in BECs and contributes to DR. Notch ligand Jagged1 is secreted from activated BECs in a Rage-dependent manner and signals HSCs in trans, eventually enhancing fibrosis during cholestasis.
2025-01-07 | GSE275751 | GEO
Project description:Following liver damage, ductular reaction and liver fibrosis often develop simultaneously. Activated hepatic stellate cells (HSC) are the main cell type in liver fibrosis development, while proliferation of hepatic progenitor cells is seen in ductular reaction. This study aims to gain insight on the interaction between these two cell types by an in vitro 3D co-culture system.
2025-04-09 | GSE264276 | GEO
Project description:Neutrophils play a central role in tissue inflammation. However, their dynamic behavior and function in chronic injury is largely unknow. Here, we show that, in chronic liver injury, neutrophils are recruited to the ductular reaction, where they are immobilized for a prolonged period of time, acquiring an aged phenotype and an altered functionality. Moreover, neutrophils depletion or inhibition of their recruitment reduced ductular reaction expansion, which was found to be NETosis and elastase-dependent. Overall, chronic liver injury alters dthe dynamics, phenotype and function of neutrophils, which promote biliary epithelium expansion and maladaptive wound-healing response.
2025-04-18 | GSE203336 | GEO
Project description:Ductular reactive (DR) cells exacerbate cholestatic liver injury and fibrosis. In this study we posited that tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) emanating from recruited macrophages restrains DR cell expansion by apoptosis, thereby limiting cholestatic liver injury. Cholestatic liver injury was induced in Wild type (WT), Trailfl/fl and in myeloid-specific Trail deleted (TrailΔmye) C57BL/6 mice using the DDC diet. The DDC diet induced injury and hepatomegaly. However, parameters of liver injury, fibrosis, ductular reaction and inflammation were all increased in the TrailΔmye mice as compared to the WT and Trailfl/fl mice. To better resolve the gene expression profile of cholangiocytes that may promote the recruitment of myeloid cells into the periportal neighborhood, we performed spatial transcriptomics on FPPE liver tissue sections from WT and TrailΔmye mice that were fed the control or DDC diet using the NanoString GeoMx DSP platform (Cat. No. 121401103, GeoMx NGS RNA WTA Mm).
2024-01-31 | GSE239667 | GEO